Homeostatic synaptic scaling adjusts a neuron's excitatory synaptic strengths up or down to compensate for perturbations in activity. This form of plasticity is expressed in large part through changes in postsynaptic AMPAR accumulation, but despite intense recent interest the complete molecular pathway(s) linking altered neuronal activity to homeostatic changes in AMPAR accumulation are not known. Recently we found that synaptic scaling up is transcription-dependent, and requires the GluR2 subunit of the AMPAR for its expression, indicating that transcription of a factor or factors results in enhanced AMPAR accumulation through interactions with GluR2. Here we will determine which GluR2 domains are essential for the homeostatic regulation of synaptic strengths, identify transcription- dependent factors that participate in the synaptic scaling pathway, and finally, use our ability to selectively block synaptic scaling to assess the role of synaptic scaling in experience-dependent plasticity in the intact visual cortex. These experiments will further our understanding of when, where, and how synaptic scaling operates within central cortical circuits, and will generate important insights into how circuits adapt during experience-driven plasticity. PUBLIC HEALTH RELEVANCE: Homeostatic synaptic scaling adjusts a neuron's excitatory synaptic strengths up or down to compensate for perturbations in activity, and acts to stabilize the function of neurons and circuits in the face of developmental or experience-dependent perturbations in drive. This form of plasticity is likely critical for maintaining stable brain function and for preventing the development of overexcitable states such as epilepsy. Despite intense recent interest in understanding the molecular pathway(s) underlying synaptic scaling, the signaling pathways and molecular players that subserve synaptic scaling are not known. The studies outlined in this grant seek to further our understanding of when, where, and how synaptic scaling operates within central cortical circuits, and will generate important insights into how circuits adapt during experience-driven plasticity. Ultimately, these studies will illuminate the genesis of aberrant states, such as addiction or epilepsy that involve adaptive plasticity and/or imbalances in synaptic excitation and inhibition.